Preparation of 2-amino-thiazole-5-carboxylic-acid derivatives

ABSTRACT

A method for preparing a compound of the structure I,

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 11/498,650 filed Aug. 3, 2006 which claims the benefit of priorityunder 35 U.S.C. § 119(b) to European Patent Application No. 05107247.8filed Aug. 5, 2005 and European Patent Application No. 05107375.7 filedAug. 11, 2005, the contents of which are herein incorporated byreference.

The present invention relates to a novel synthetic route to2-amino-thiazole-5-carboxylic-acid-aryl amides of the formula I.

Aryl-substituted 2-Amino-5-thiazole-carboxamides of the type of theCompounds of Formula I are known from U.S. Pat. No. 6,596,746 asintermediates in the synthesis of pharmaceutical active ingredients. Thecompounds are obtained by reaction of an amine-protected thiazolecarboxylic acid chloride with a substituted aniline in the presence of abase followed by removal of the amine protective group.

According to EP-A 275 312 substituted amino thiazoles can be obtained byreaction of substituted thiourea with an α-chloro carbonyl compoundwherein the carbonyl compound may be protected as a dialkyl acetal.

According to US Statutory Invention Registration No. H1737 compounds ofthe type of Formula II are disclosed as intermediates in the synthesisof pharmaceutical active ingredients.

The reaction of dichloroacrylic acid chloride with amines such as6-Chloro-2-methyl-aniline is disclosed in DE-A 2436653.

The object of the present invention was to find an improved method formaking compounds of the Formula I.

The present invention provides for an improved method for preparing acompound of the structure I,

wherein R is aryl, substituted with one or more residues selected fromthe group consisting of chlorine, methyl, ethyl, methoxy and ethoxy,which comprises providing a compound of the structure II

and reacting the above compound with substituted anilines of thestructure III,

wherein R has the same meaning as above, in the presence of an inorganicbase and subjecting the reaction mixture to a reaction with analkanolate salt to give a compound of formula IV,

which compound is reacted with thiourea in an acidic medium to give thecompound of formula I.

The present invention also provides for novel intermediates of formulaIV.

The starting compound dichloro acrylic acid chloride II can be obtainedin any known manner, for instance by alkaline hydrolysis of mucochloricacid to 2,3-dichloro acrylic acid and further reaction to the acidchloride (Compound II).

The overall synthetic route can be carried out as outlined in thefollowing simplified scheme A:

Compound II is reacted with a substituted aniline of formula III in thepresence of an inorganic base and a solvent system. Preferredsubstituted anilines are 6-Chloro-2-methyl aniline or 2-methyl anilineor 3-methyl aniline or 4-methyl aniline or 4,6-dichloro-2-methylaniline.

Suitable bases comprising an acidic moiety such as hydrogencarbonate,hydrogenphosphate or acetate include ammonium salts, alkali metal saltssuch as sodium, lithium or potassium salts, or alkaline earth metals,such as calcium or magnesium salts, preferably sodium hydrogencarbonateor potassium hydrogencarbonate. The solvent system is preferably amixture of water and an organic solvent capable of forming a biphasicmixture with water such as C₅-C₈ alkanes, C₄-C₈ ether, C₄-C₈ ester orC₆-C₉ alkylaromates preferably, toluene. The molar ratio of the amountof base used in this reaction is 1 to 10.

The immediate reaction product (Compound IIIa) of the reaction between2,3-dichloro acryloyl chloride and the substituted aniline III is notisolated from the reaction mixture. The reaction mixture comprising suchreaction product IIIa is subsequently treated with an alkanolate salt togive the compound of formula IV. Alkanolysis is preferably carried outin the presence of the sodium or potassium salts of C₁-C₆-alkanols orC₂-C₇-alkanediols, sodium methanolate being the most preferredalkanolate salt. The respective alkanol is preferably used as solventfor the reaction. The molar ratio of the amount of alkanolate salt usedin this reaction is 1-5.

The compound of formula IV is reacted with thiourea in an acidic mediumto give the target compound I. The acidic medium is provided by thepresence of a strong acid. Suitable strong acids are hydrochloric acidor hydrobromic acid, preferably hydrochloric acid. The reaction can becarried out in a solvent such as formic acid, acetic acid, propionicacid or trifluoro acetic acid.

In a preferred method the reaction is carried out in a mixture of HCl asan acid and acetic acid as the solvent. The molar ratio of acid tocompound IV is 1-10.

The resulting thiazole derivative is obtained as the salt of the strongacid, from which the free base can be obtained by any known manner, forinstance by treating the salt with a base. The preferred base is sodiummethanolate.

Purification of the target compound can be carried by recrystallization.

Preferably, purification is carried out by recrystallization in solventssuch as C₅-C₈ alkanes, C₄-C₈ ether, C₄-C₈ ester, C₁-C₆ alcohols or C₆-C₉alkylaromates and water, preferably THF, hexane, methanol and water ormixtures thereof. Preferably the recrystallization is carried out attemperatures from −20 to 100° C., especially 0 and 60° C.

All steps of the synthesis are carried out under reflux of therespective solvent used in each step at 40 to 70° C., preferably at 50to 65° C. The reaction can be carried out at atmospheric pressure.

Preferably the invention provides for an improved method as outlined inthe following scheme B:

According to the inventive method the target molecule can be produced inhigh yields and high purities.

Additionally, the compounds of Formula I may be useful in thepreparation of the compound of formula V, see the following Scheme C:

The compound of Formula V may be prepared as described in WO00/62778,and in WO2005/077945, which are hereby incorporated by reference.

EXAMPLE 1 Preparation of 2,3-dichloro acrylic acid

A 4000 1 vessel was charged with 1800 1 of demineralized water and 460kg of caustic soda (50 wt. % aqueous solution) and heated to 40° C.while stirring. Within 2 hours 400 kg of mucochloric acid were added tothe reaction mixture with the temperature of the reaction mixturevarying from 10 to 50° C. After the addition had been completed thereaction mixture was stirred for 1 hour at 40° C. The vessel was cooledto 25° C. and 600 1 hydrochloric acid (37% b.w., aqueous) were added.Afterwards the reaction mixture was cooled to 0° C. and stirred at thattemperature for one hour. The resulting suspension was filtered by acentrifuge. Yield: 67%.

EXAMPLE 2 Preparation of a 2,3-dichloro acrylic chloride

A 2000 1 reaction vessel was charged with 165 kg muco chloric acid, 400kg toluene and 0.85 kg DMF. Then 420 kg thionylchloride is added at 70°C. within 4 h. After gas evolution has ceased thionylchloride andtoluene were distilled off at reduced pressure. Afterwards the productwas distilled at 95° C./50 mbar. Yield: 87%.

EXAMPLE 3 Preparation of a2-chloro-N-(2-chloro-6-methyl-phenyl)-3,3-dimethoxy-propionamide

A 4000 1 vessel was charged with 187 kg of potassium hydrogencarbonateand 561 1 of water under a nitrogen atmosphere. After the mixture hadbeen stirred at ambient temperature for half an hour 156 kg of2-chloro-6-methyl-aniline and 193 1 of toluene were added and themixture heated to 60-65° C. Then 280 kg of a 75% b.w. solution of 2,3dichloro acryloyl chloride in toluene were added within four hours andthe reaction mixture was stirred for additional two hours. Then 440 1toluene were charged into the vessel and the phases were separated.During addition of the dichloro acryloyl chloride solution, additionalstirring and phase separation the temperature was kept at 60-65° C. Theorganic phase was subjected to vacuum distillation and water and toluenewere distilled off. 1375 1 of methanol were charged into the vessel anddistillation was continued until the residual toluene was removed. Then198 kg of a 30% b.w. solution of sodium methanolate in methanol wereadded at 50° C. within two hours and the resulting mixture stirred foranother five hours at 50° C. The mixture was cooled to 20-25° C. and 1101 of methanol were distilled off at 500 mbar.

EXAMPLE 4 Preparation of 2-Amino-thiazole-5-carboxylic acid(2-chloro-6-methyl-phenyl)-amide

The vessel with the product obtained according to Example 2 was purgedwith nitrogen and the reaction mixture diluted with 1023 1 of aceticacid. Residual methanol was distilled off as a mixture with acetic acid.After 253 1 of acetic acid and 109 kg of hydrochloric acid (37% b.w. ofHCl) had been added at 50° C. 92 kg of thiourea were charged into thevessel and the reaction mixture heated to 60-65° C. and stirred foreleven hours. About 715 1 of acetic acid were distilled off at 100 mbarand 847 1 of methanol were added. After about 780 1 of a methanol/aceticacid mixture had been distilled off at atmospheric pressure 847 1 ofmethanol and 135 kg of a 30% b.w. solution of sodium methanolate inmethanol were added in portions to adjust the pH at pH 8-9. Theprecipitated salts were filtered off and the filtrate was treated with125 kg charcoal at 60° C. for several hours. After removal of thecharcoal by filtration 1000 1 methanol are distilled off at 500 mbar.Then 2000 1 water are added and the reaction mixture in cooled down to0° C. The product is filtered off. The filter cake was dried by purgingit with nitrogen at 50° C.

In a 4000 1 vessel 130 kg of the crude thiazol are dissolved in 870 kgTHF at 50° C. and 640 kg hexane are added at 20° C. within 3 h. thesuspension is cooled down to 0° C. and the product is filtered off. thefilter cake is washed with 380 1 hexane and dried in a drying chamber.Overall Yield: 68%.

1. A method for preparing a compound of the structure V

which comprises providing a compound of the structure II

and reacting the above compound with substituted anilines of thestructure III,

in the presence of an inorganic base and subjecting the reaction mixtureto a reaction with an alkanolate salt to give a compound of formula IV,

which compound is reacted with thiourea in an acidic medium to give thecompound of formula I,

the compound of formula I is reacted with4,6-dichloro-2-methyl-pyrimidine, followed by 2-piperazin-1-yl-ethanolto give the compound of formula V.
 2. A method as defined in claim 1,wherein the base is sodium hydrogencarbonate or potassiumhydrogencarbonate.
 3. A method as defined in any of claim 2, wherein thealkanolate salt is sodium methanolate.
 4. A method as defined in any ofclaim 3, wherein the starting compound II is prepared by alkalinehydrolysis of mucochloric acid and subsequent formation of the acylchloride of 2,3-dichloro acrylic acid.